In order to obtain a drug action, there are two means, in which the drug is administered orally, or administered transdermally. Transdermal administration has a number of advantages over oral administration. For example, in oral administration method of drug, the drug absorbed from intestine is first metabolized at liver before it presents its action at a desired place, and a large amount thereof is degraded, whereas transdermal administration method has an advantage that the absorbed drug does not pass liver first when circulating in the body, so that its drug action is not decreased severely by the metabolism at liver.
Further, transdermal administration method has another advantage that it provides a continued drug effect, and it has a constant drug release property.
For example, the drug of the general formula (1)
wherein R is 2-isopropoxyethoxymethyl group (bisoprolol), carbamoylmethyl group (atenolol) or 2-methoxyethyl group (metoprolol), is a β-blocker and a therapeutic drug of essential hypertension that selectively blocks β1 receptor of sympathetic nervous system, and does not have intrinsic sympathetic nervous stimulating action.
Although the above therapeutic drugs are only used as oral drugs in the clinical site at present, bisoprolol (R: 2-isopropoxyethoxymethyl group), among the drugs represented by general formula (1), in particular, has relatively little effects on bronchi due to the high β1 selectivity. However, when bisoprolol is administered orally, symptoms such as bradycardia, dizziness and feeling of weariness may occur, and from the view point of stabilization of drug levels in the blood and a continuous drug effect, development of a preparation for transdermal administration in the form of adhesive patch and the like rather than the one for oral administration is desired.
Taking such a state into consideration, as a transdermal patch controlling the release property of the drug, it has been proposed to control it by making the adhesive base in laminated form (Patent document 1 and Patent document 2). Patent document 1 describes a laminate-type transdermal patch wherein a fine powder such as of titanium oxide, silica and aluminum silicate together with a drug in an adhesive layer that does not contact with skin. However, this preparation has the problems that the fine powder may be involved in various reactions such as degradation of drug and base, and that physical property necessary for the adhesive agent such as adherability and cohesiveness is impaired.
Further, Patent document 2 describes that a predetermined amount of a drug is absorbed transdermally continuously by laminating an adhesive layer of natural rubber, synthetic rubber, acrylic resin and the like having a similar solubility parameter to that of the drug. However, this laminate-type adhesive agent has the problems that the drug is prone to move between laminates, and in the actual use, the drug cannot be released in a controlled manner, because it is necessary to laminate the adhesive agent layer with a similar property so that every adhesive layer to be laminated can comprise a high concentration of a drug, and it has also the problem that the availability of the drug is low and the cost of production increases because the adhesive agent with a high solubility of a drug is used. Moreover, it has the problem that adhesive properties are deteriorated by the drug concentration that is higher than the saturation concentration.
Further, embodiments for controlling the releasing property of bisoprolol are disclosed for example in Patent documents 3 to 5. In Patent document 3, the art of preventing a decrease of cohesion caused by sweating from the skin using acryl/acryl laminate is disclosed, but in the viewpoint of controlling drug release, because acryl/acryl laminate has very similar chemical properties between layers, it had the problem that the drug is prone to move between layers, and in the case of practical use, it cannot provide the drug in a sustained manner.
Further, Patent document 4 discloses that the laminate of rubber/fluorine-containing polymer prevents the recrystallization of the drug by providing a layer with lower diffusion rate to the skin side, and Patent document 5 discloses that the laminate of high-molecular-weight polymer/amorphous prevents cold flow of the adhesive patch by utilizing the difference in glass transition point. However, these known prior arts do not describe the drug release property at all, and had the problem that the production process is complicated because a large number of layers are laminated.    [Patent document 1] JP, A, 5-271056    [Patent document 2] JP, A, 6-205839    [Patent document 3] JP, A, 2004-10525    [Patent document 4] JP, A, 11-512080    [Patent document 5] JP, A, 2003-507417